EP2147922B1 - Dérivé hétérocyclique condensé, composition pharmaceutique comprenant le dérivé et utilisation de la composition pour des objectifs médicaux - Google Patents

Dérivé hétérocyclique condensé, composition pharmaceutique comprenant le dérivé et utilisation de la composition pour des objectifs médicaux Download PDF

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EP2147922B1
EP2147922B1 EP08740472.9A EP08740472A EP2147922B1 EP 2147922 B1 EP2147922 B1 EP 2147922B1 EP 08740472 A EP08740472 A EP 08740472A EP 2147922 B1 EP2147922 B1 EP 2147922B1
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group
substituent
lower alkyl
ring
fused heterocyclic
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EP2147922A1 (fr
EP2147922A4 (fr
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Kohsuke Ohno
Noboru Kamada
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Kissei Pharmaceutical Co Ltd
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Kissei Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones

Definitions

  • the present invention relates to fused heterocyclic derivatives.
  • the present invention relates to fused heterocyclic derivatives which have an antagonistic activity against gonadotropin releasing hormone and can be used for the prevention or treatment of a sex hormone-dependent disease such as benign prostatic hypertrophy, hysteromyoma, endometriosis, metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea or the like, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same and the like.
  • a sex hormone-dependent disease such as benign prostatic hypertrophy, hysteromyoma, endometriosis, metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea or the like, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same and the like.
  • GnRH Gonadotropin Releasing Hormone
  • LHRH Luteinizing Hormone Releasing Hormone
  • GnRH is a peptide consisting of 10 amino acids: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH 2 ), which is secreted from the hypothalamus.
  • GnRH secreted into hypophyseal portal vein promotes the production and secretion of gonadotropin of anterior pituitary hormones, Luteinizing Hormone: LH and Follicle Stimulating Hormone: FSH, via the receptors which are considered to exist in the anterior lobe of the pituitary, GnRH receptor.
  • LH and FSH Follicle Stimulating Hormone
  • FSH Follicle Stimulating Hormone
  • gonadotropins affect gonad, ovary and testis, to promote the folliclar growth, ovulation and luteinization and spermatogenesis and also promote the production and secretion of sex hormones such as estrogen, progesterone and androgen (see Non-patent reference 1).
  • antagonists specifically and selectively acting on the GnRH receptors should control the activities of GnRH and control the production and secretion of gonadotropin and sex hormones, and therefore, are expected to be useful as an agent for the prevention or treatment of sex hormone-dependent diseases.
  • GnRH receptor superagonists As an agent inhibiting the function of GnRH receptor, GnRH receptor superagonists (hereinafter referred to as "GnRH superagonist”) have been used as agents for the treatment of sex hormone-dependent diseases such as prostatic cancer, breast cancer, endometriosis and the like.
  • the GnRH superagonists bind GnRH receptors and exert an initial temporary gonadotropin secretion-stimulating effect so-called “flare-up phenomenon", and then suppress the function by causing gonadotropin depletion and GnRH receptor down-regulation to suppress. Therefore, the GnRH receptor superagonists have a problem that the disease becomes exacerbated transiently by the initially promoted secretion of gonadotropin.
  • GnRH antagonist GnRH receptor antagonists
  • GnRH antagonists peptidic GnRH antagonists such as abarelix and cetrorelix have been developed and used for the treatment of prostatic cancer, infertility and the like.
  • these peptidic GnRH antagonists have bad oral absorbability, they have to be subcutaneously or intramuscularly administered.
  • development of a non-peptidic GnRH antagonist which can be orally administered wherein local reactivity at injected sites can be reduced and the dosages can be flexibly adjusted is desired (see Non-patent reference 2).
  • the present invention aims to provide a compound which has a GnRH antagonistic activity.
  • a pyrimidine derivative fused with a 5-membered hetero ring represented by the following general formula (I) has an excellent GnRH antagonistic activity and exerts an excellent pharmacokinetics in blood by oral administration in comparison with a pyrimidine derivative fused with a 6-membered aromatic ring, thereby forming the basis of the present invention.
  • the present invention relates to:
  • a fused heterocyclic derivative (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent GnRH antagonistic activity, it can control the effect of gonadotropin releasing hormone and control the production and secretion of gonadotropin and sex hormones, and as a result, it can be used as an agent for the prevention or treatment of sex hormone-dependent diseases.
  • heteroaryl means monocyclic heteroaryl having 1 or more hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom such as thiazole, oxazole, isothiazole, isoxazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, furazan or the like.
  • aryl means phenyl
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or a iodine atom.
  • lower alkyl means optionally branched alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, tert -butyl, pentyl, isopentyl, neopentyl, tert -pentyl, hexyl or the like.
  • lower alkylene means optionally branched alkylene having 1 to 6 carbon atoms such as methylene, ethylene, methylmethylene, trimethylene, dimethylmethylene, ethylmethylene, methylethylene, propylmethylene, isopropylmethylene, dimethylethylene, butylmethylene, ethylmethylmethylene, pentamethylene, diethylmethylene, dimethyltrimethylene, hexamethylene, diethylethylene or the like.
  • C 1-3 alkylene means the above lower alkylene having 1 to 3 carbon atoms.
  • lower alkoxy means optionally branched alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec -butoxy, tert -butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert -pentyloxy, hexyloxy or the like.
  • (lower alkoxy)carbonyl means an optionally branched alkoxycarbonyl group having 2 to 7 carbon atoms.
  • (lower alkyl)thio means optionally branched alkylthio having 1 to 6 carbon atoms.
  • cycloalkyl means monocyclic cycloalkyl having 3 to 8 carbon atoms, for example, monocyclic cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be illustrated.
  • heterocycloalkyl means 3 to 8-membered heterocycloalkyl having 1 or more hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and optionally having 1 or 2 oxo groups such as pyrrolidinyl, piperidinyl, oxopiperidinyl, morpholinyl, piperazinyl, oxopiperazinyl, thiomorpholinyl, azepanyl, diazepanyl, oxazepanyl, thiazepanyl, dioxothiazepanyl, azokanyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl or the like.
  • the sulfur atom may be oxidized.
  • fused means which may be fused with a ring selected from the group consisting of the above cycloalkyl, the above heterocycloalkyl, the above aryl and the above heteroaryl.
  • fused cycloalkyl means which may be fused with a ring selected from the group consisting of the above cycloalkyl, the above heterocycloalkyl, the above aryl and the above heteroaryl.
  • fused cycloalkyl means which may be fused with a ring selected from the group consisting of the above cycloalkyl, the above heterocycloalkyl, the above aryl and the above heteroaryl.
  • fusedolyl isoindolyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, indazolyl, benzimidazolyl, quinolinyl
  • cyclic amino means a group having at least a nitrogen atom which is a binding site in the ring among the above optionally fused heterocycloalkyl.
  • (di)(lower alkyl)amino means amino mono- or di-substituted by the above lower alkyl. Two lower alkyl groups in di-substituted amino may be different and the two lower alkyl groups may bind together to form a cyclic amino group with the neighboring nitrogen atom.
  • (di)(lower alkyl)carbamoyl means carbamoyl mono- or di-substituted by the above lower alkyl.
  • Two lower alkyl groups in di-substituted carbamoyl may be different and the two lower alkyl groups may bind together to form a cyclic amino group with the neighboring nitrogen atom.
  • acyl means optionally branched aliphatic carboxylic acyl having 2 to 7 carbon atoms, cycloalkylcarboxylic acyl, heterocycloalkylcarboxylic acyl, arylcarboxylic acyl, or heteroarylcarboxylic acyl.
  • acylamino means amino substituted by the above acyl.
  • thiophene rings represented by the following formula: are particularly preferable.
  • R A a lower alkyl group substituted by a group selected from the group consisting of a hydroxy group, a carboxy group and a carbamoyl group; a carboxy group; or a carbamoyl group is preferable, and a carboxy group is even more preferable.
  • m is 1, as ring A having R A on the ring, thiophene rings represented by the following formula: are particularly preferable.
  • R A an optionally substituted lower alkyl group, -COOW 1 or -CONW 2 W 3 in which W 1 to W 3 independently represent a hydrogen atom or an optionally substituted lower alkyl group, or W 2 and W 3 optionally bind together to form an optionally substituted cyclic amino group with the neighboring nitrogen atom, is more preferable.
  • ring B a benzene ring or a thiophene ring is more preferable.
  • the binding position of ring B is preferably as represented by the following formula: and in particular, is preferably as represented by the following formula: wherein the left bond represents a bond with the nitrogen atom of the fused pyrimidine ring and the right bond represents a bond with the nitrogen atom of -N(Q)(X).
  • n 1 or 2
  • a benzene ring, a thiophene ring or a pyridine ring represented by the following formula: wherein the left bond of the bonds not bound to any of R B represents a bond with the nitrogen atom of the fused pyrimidine ring and the right bond represents a bond with the nitrogen atom of -N(Q)(X) is preferable.
  • R B a fluorine atom, a chlorine atom or -OW 4 in which W 4 is a lower alkyl group is particularly preferable.
  • two R B may be the same or different.
  • ring B having R B on the ring is a benzene ring, a thiophene ring or a pyridine ring represented by the following formula: wherein the left bond of the bonds not bound to any of R B1 and R B2 represents a bond with the nitrogen atom of the fused pyrimidine ring and the right bond represents a bond with the nitrogen atom of -N(Q)(X), as R B1 , a fluorine atom or a chlorine atom is preferable, and as R B2 , a fluorine atom, a methoxy group or an ethoxy group is preferable, and a methoxy group is more preferable.
  • a C 1-3 lower alkylene group is more preferable.
  • an optionally substituted aryl group may have, a halogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group is preferable, and a halogen atom; a lower alkyl group optionally substituted by a halogen atom, a lower alkoxy group or a hydroxy group; or a lower alkoxy group optionally substituted by a halogen atom, a lower alkoxy group or a hydroxy group, is more preferable.
  • the optionally substituted cyclic amino group may have one or the same or different two or more substituents.
  • the optionally substituted aryl group may have one or the same or different two or more substituents.
  • an optionally fused and optionally substituted cycloalkyl group an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group and an optionally fused and optionally substituted heteroaryl group
  • the substituents optionally exist on the same or different rings in the fused ring.
  • the optionally substituted lower alkyl, optionally substituted lower alkylene, optionally substituted lower alkoxy, optionally substituted (lower alkyl)thio or optionally substituted (lower alkoxy)carbonyl group may have one or the same or different two or more substituents.
  • a compound wherein E 1 is an oxygen atom can be prepared, for example, by Method 1.
  • R 1 represents a nitrile group or a (lower alkoxy)carbonyl group
  • ring A, ring B, R A , R B , m, n, E 2 , Q and X have the same meanings as defined above.
  • Amine compound (1) can be converted by allowing to react in an inert solvent such as tetrahydrofuran, methylene chloride, a mixed solvent thereof or the like using a reagent such as phosgene, diphosgene, triphosgene or the like in the presence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine or the like usually under ice-cooling to at reflux temperature for 30 minutes to 1 day into Isocyanate compound (2).
  • an inert solvent such as tetrahydrofuran, methylene chloride, a mixed solvent thereof or the like
  • a reagent such as phosgene, diphosgene, triphosgene or the like
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine or the like usually under ice-cooling to at reflux temperature for 30 minutes to 1 day into Isocyanate compound (2).
  • Urea compound (4) or a fused heterocyclic derivative of the present invention (Ia) can be prepared by allowing Isocyanate compound (2) and Amine compound (3) to react in an inert solvent such as tetrahydrofuran, methylene chloride, a mixed solvent thereof or the like in the presence or absence of a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 4-dimethylaminopyridine or the like usually under ice-cooling to at reflux temperature for 1 hour to 3 days.
  • an inert solvent such as tetrahydrofuran, methylene chloride, a mixed solvent thereof or the like
  • a base such as triethylamine, N,N- diisopropylethylamine, pyridine, 4-dimethylaminopyridine or the like usually under ice-cooling to at reflux temperature for 1 hour to 3 days.
  • a fused heterocyclic derivative of the present invention (Ia) also can be prepared by allowing Urea compound (4) to react in an inert solvent such as tetrahydrofuran, methylene chloride, methanol, ethanol, N,N -dimethylformamide, water, a mixed solvent thereof or the like in the presence or absence of a base such as triethylamine, N,N -diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium methoxide, sodium ethoxide, sodium hydride, sodium hydroxide, lithium hydroxide or the like usually under ice-cooling to at reflux temperature for 5 minutes to 3 days.
  • an inert solvent such as tetrahydrofuran, methylene chloride, methanol, ethanol, N,N -dimethylformamide, water, a mixed solvent thereof or the like
  • a base such as triethylamine, N,N -diisopropy
  • a compound wherein E 2 is an oxygen atom can be prepared, for example, by Method 2.
  • ring A, ring B, R A , R B , m, n, Q and X have the same meanings as defined above.
  • Amide compound (6) can be prepared by condensing Carboxylic acid compound (5) and Amine compound (3) by a general carboxylic chloride method or condensing agent method.
  • a carboxylic chloride method can be conducted, for example, by treating Carboxylic acid compound (5) in an inert solvent such as methylene chloride, 1,2-dichloroethane, toluene, a mixed solvent thereof or the like using a reagent such as thionyl chloride, oxalyl chloride or the like in the presence or absence of an additive such as N,N- dimethylformamide or the like usually under ice-cooling to at reflux temperature for 30 minutes to 1 day to derive into the carboxylic chloride, and followed by allowing to react with Amine compound (3) in an inert solvent such as pyridine, methylene chloride, tetrahydrofuran, water, a mixed solvent thereof or the like in the presence or absence of a base such as triethylamine, N,N
  • a condensing agent method can be conducted, for example, by allowing Carboxylic acid compound (5) and Amine compound (3) to react in an inert solvent such as N,N- dimethylformamide, methylene chloride, tetrahydrofuran, a mixed solvent thereof or the like using an condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide or the like in the presence of an additive such as 1-hydroxybenzotriazole or the like in the presence or absence of a base such as triethylamine, N,N -diisopropylethylamine, pyridine, 4-dimethylaminopyridine or the like usually at from room temperature to reflux temperature for 1 hour to 3 days.
  • an inert solvent such as N,N- dimethylformamide, methylene chloride, tetrahydrofuran, a mixed solvent thereof or the like
  • Amine compound (7) can be prepared by reducing the nitro group of Amide compound (6) by a general catalytic reduction method, a metal hydride complex reduction method or the like.
  • a catalytic reduction method can be conducted, for example, by treating Amide compound (6) under a hydrogen atmosphere in an inert solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, a mixed solvent thereof or the like using a catalyst such as palladium-carbon powder or the like usually at from room temperature to reflux temperature for 1 hour to 3 days.
  • a metal hydride complex reduction method can be conducted, for example, by treating Amide compound (6) in an inert solvent such as methanol, ethanol, tetrahydrofuran, a mixed solvent thereof or the like using a reducing agent such as sodium borohydride or the like in the presence of an additive such as nickel(II) bromide or the like usually under ice-cooling to at room temperature for 30 minutes to 1 day.
  • an inert solvent such as methanol, ethanol, tetrahydrofuran, a mixed solvent thereof or the like
  • a reducing agent such as sodium borohydride or the like
  • an additive such as nickel(II) bromide or the like usually under ice-cooling to at room temperature for 30 minutes to 1 day.
  • a fused heterocyclic derivative of the present invention (Ib) can be prepared by treating Amine compound (7) in an inert solvent such as tetrahydrofuran, methylene chloride, N,N- dimethylformamide, a mixed solvent thereof or the like using a reagent such as phosgene, diphosgene, triphosgene, 1,1'-carbonylbis- 1H- imidazole or the like in the presence or absence of a base such as triethylamine, N,N -diisopropylethylamine, pyridine, 4-dimethylaminopyridine, sodium hydride or the like usually under ice-cooling to at reflux temperature for 30 minutes to 1 day.
  • an inert solvent such as tetrahydrofuran, methylene chloride, N,N- dimethylformamide, a mixed solvent thereof or the like
  • a reagent such as phosgene, diphosgene, triphosgene, 1,1'-carbony
  • a fused heterocyclic derivative of the present invention (Ic) can be prepared by treating Amine compound (7) in an inert solvent such as tetrahydrofuran, N,N -dimethylformamide, methanol, ethanol, a mixed solvent thereof or the like using a reagent such as carbon disulfide or the like in the presence of a base such as triethylamine, N,N- diisopropylethylamine, sodium hydride, sodium hydroxide, potassium hydroxide or the like usually under ice-cooling to at reflux temperature for 1 hour to 3 days.
  • an inert solvent such as tetrahydrofuran, N,N -dimethylformamide, methanol, ethanol, a mixed solvent thereof or the like
  • a reagent such as carbon disulfide or the like
  • a base such as triethylamine, N,N- diisopropylethylamine, sodium hydride, sodium hydroxide, potassium hydroxide
  • a fused heterocyclic derivative of the present invention (Id) can be prepared by treating Amine compound (7) in an inert solvent such as tetrahydrofuran, N,N- dimethylformamide, methanol, ethanol, a mixed solvent thereof or the like using a reagent such as diphenylcyanocarbonimidate or the like in the presence of a base such as triethylamine, N,N- diisopropylethylamine, sodium hydride, sodium hydroxide, potassium hydroxide or the like usually under ice-cooling to at reflux temperature for 1 hour to 3 days.
  • an inert solvent such as tetrahydrofuran, N,N- dimethylformamide, methanol, ethanol, a mixed solvent thereof or the like
  • a reagent such as diphenylcyanocarbonimidate or the like
  • a base such as triethylamine, N,N- diisopropylethylamine, sodium hydride, sodium hydroxide,
  • Amine compound (3) used as a starting material in the above Method 1 or 2 also can be obtained, for example, by reducing Nitro compound (8), which is commercially available or synthesized by a method described in literatures, combining general synthetic methods or the like, by a general reduction method or the like. For example, it can be prepared by the following Method 3.
  • ring B, R B , n, Q and X have the same meanings as defined above.
  • Amine compound (3) can be prepared by reducing Nitro compound (8) by a general catalytic reduction method, a metal hydride complex reduction method or the like.
  • a catalytic reduction method can be conducted, for example, by treating Nitro compound (8) under a hydrogen atmosphere in an inert solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, a mixed solvent thereof or the like using a catalyst such as palladium-carbon powder, rhodium-carbon powder, platinum-carbon powder or the like usually at from room temperature to reflux temperature for 1 hour to 3 days.
  • a metal hydride complex reduction method can be conducted, for example, by treating Nitro compound (8) in an inert solvent such as methanol, ethanol, tetrahydrofuran, a mixed solvent thereof or the like using a reducing agent such as sodium borohydride or the like in the presence of an additive such as nickel(II) bromide or the like usually under ice-cooling to at room temperature for 30 minutes to 1 day.
  • an inert solvent such as methanol, ethanol, tetrahydrofuran, a mixed solvent thereof or the like
  • a reducing agent such as sodium borohydride or the like
  • an additive such as nickel(II) bromide or the like usually under ice-cooling to at room temperature for 30 minutes to 1 day.
  • a compound used or prepared in the above Methods has a functional group which changes under the reaction conditions or inhibits the reaction progression, needless to say, the group may be protected by an appropriate protective group a commonly used by a skilled person in the art and the protective group may be removed in an appropriate step.
  • a fused heterocyclic derivative represented by the general formula (I) can be converted into a pharmaceutically acceptable salt thereof in the usual way.
  • a salt for example, a salt with an inorganic acid such as hydrochloric acid, nitric acid or the like; a salt with an organic acid such as acetic acid, methanesulfonic acid or the like; and a sodium salt and a potassium salt; an additive salt with an organic base such as N,N' -dibenzylethylenediamine, 2-aminoethanol or the like can be illustrated.
  • a fused heterocyclic derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof sometimes can be obtained as a hydrate or solvate in the course of purification or preparing salts thereof.
  • a fused heterocyclic derivative represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof includes a hydrate thereof or a solvate thereof with a pharmaceutically acceptable solvent.
  • a pharmaceutically acceptable solvent ethanol or the like can be illustrated.
  • a fused heterocyclic derivative represented by the general formula (I) there can be tautomers, geometrical isomers and/or optical isomers.
  • any of the isomers and a mixture thereof can be employed.
  • a fused heterocyclic derivative (I) of the present invention has an excellent GnRH antagonistic activity and can control the effect of gonadotropin releasing hormone and control the production and secretion of gonadotropin and sex hormones.
  • a fused heterocyclic derivative (I) of the present invention or a pharmaceutically acceptable salt thereof is extremely useful as an agent for the prevention or treatment of sex hormone-dependent diseases such as benign prostatic hypertrophy, hysteromyoma, endometriosis, metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosis, hirsutism, short stature, sleep disorders, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome, prostatic cancer, uterine cancer, ovary cancer, breast cancer and pituitary tumor; a reproduction regulator, a contracept
  • a Pharmaceutical composition may be prepared by mixing a fused heterocyclic derivative (I) of the present invention or a pharmaceutically acceptable salt thereof, and a conventional pharmaceutical carrier.
  • the pharmaceutical carrier may be used optionally in combination according to a dosage form as described below.
  • excipients such as lactose or the like; lubricants such as magnesium stearate or the like; disintegrators such as carboxymethylcellulose or the like; binders such as hydroxypropylmethylcellulose or the like; surfactants such as macrogol or the like; foamings such as sodium hydrogen carbonate or the like; dissolving aids such as cyclodextrin or the like; acidities such as citric acid or the like; stabilizers such as sodium edetate or the like; pH adjusters such as phosphoric acid salt or the like can be illustrated.
  • formulations for oral administration such as powders, granules, fine granules, dry syrups, tablets, capsules and the like; formulations for parenteral administration such as injections, poultices, suppositories and the like are illustrated, and a formulation for oral administration is preferable.
  • the dosage of the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is appropriately within the range of from 0.1 to 1,000 mg per day per adult human in case of oral administration and approximately within the range of from 0.01 to 100 mg per day per adult human in the case of parenteral injection in the formulation.
  • a pharmaceutical composition of the present invention can include other drug(s).
  • other drugs include a GnRH superagonist(for example, leuprorelin acetate, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin, lecirelin and the like), a chemotherapeutic agent (for example, ifosfamide, adriamycin, peplomycin, cisplatin, cyclophosphamide, 5-FU, UFT, methotrexate, mitomycin C, mitoxantrone, paclitaxel, dotaxel and the like), a peptidic GnRH antagonist (for example, cetrorelix, ganirelix, abarelix, ozarelix, iturelix, degarelix, teverelix and the like), a 5 ⁇ -reductase inhibitor (for example, finaster
  • Tables 1 to 3 and Tables 4 to 5 show the chemical structure and 1 H-NMR data of the above compounds of Reference Examples 1 to 18 and Examples 1 to 14, respectively.
  • the expression vector of human GnRHR1 gene was digested by XhoI into a linear DNA.
  • the linear DNA was transfected into HEK293 cells by means of lipofection (Lipofectamine2000: Invitrogen).
  • Neomycin resistant cell lines were selected by culture in the medium containing G418 (Invitrogen) at 1 mg/mL, and then the change of calcium levels in GnRH-stimulated cells was measured by the method described below.
  • the cell line, which showed the greatest change was selected and designated as hGnRHR1#1.
  • hGnRHR1#1 cells were cultured in the presence of G418 at 0.5 mg/mL.
  • hGnRHR1#1 cells were seeded into a 96-well culture plate at a density of 1.5 x 10 5 cells/well and cultured for a day. After removing the culture medium, cells were washed with 200 ⁇ L per well of the washing buffer (Hanks' Balanced Salt Solutions, 20 mM N -2-hydroxyethylpiperazine- N' -2-ethanesulfonic acid, 1.3 mM calcium chloride, 0.5 mM magnesium chloride, 0.4 mM magnesium sulfate).
  • test compound was dissolved by adding 0.2 mL of N,N- dimethylacetoamide, 9.794 mL of 0.5 % aqueous methylcellulose solution and 0.006 mL of 2N NaOH, and then 0.3 mg/mL solution was prepared.
  • the body weights of rats were measured, and the solution of the test compound was administered orally at the dose of 10 mL/kg (3 mg/kg).
  • the oral administration was performed with gastric tube for rat and 2.5 mL syringe.
  • the sampling times for collection of blood were 15, 30, 60, 120, 240 and 360 minutes after the oral administration.
  • the blood was centrifuged, and the plasma was used as the sample for measurement of the drug concentration in blood.
  • Control compound 1 is the sulfonamide compound of Example 15 described in the above Patent reference 3.
  • a fused heterocyclic derivative of the present invention is more superior in blood kinetics such as availability and sustainability by oral administration than the Control compound.
  • the fused heterocyclic derivatives of Examples 1 and 2 exert more excellent availability than the Control compound 1, and thus, is more preferable as a pharmaceutical composition for oral administration.
  • the fused heterocyclic derivatives of Examples 1 and 2 maintain their blood concentrations 6 hours after the oral administrations and more superior in sustainability than the Control compound. Therefore, the fused heterocyclic derivatives of the present invention can be used as a long-acting preparation substantially without a sustained-release base such as hydroxyalkylcellulose, alkylcellulose or the like.
  • a fused heterocyclic derivative (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent GnRH antagonistic activity, and thus, can be used as an agent for the prevention or treatment of sex hormone-dependent diseases by controlling the effect of gonadotropin releasing hormone and controlling the production and secretion of gonadotropin and sex hormones.
  • the present invention can provide an agent for the prevention or treatment of benign prostatic hypertrophy, hysteromyoma, endometriosis, metrofibroma, precocious puberty, amenorrhea, premenstrual syndrome, dysmenorrhea, polycystic ovary syndrome, lupus erythematosis, hirsutism, short stature, sleep disorders, acne, baldness, Alzheimer's disease, infertility, irritable bowel syndrome, prostatic cancer, uterine cancer, ovary cancer, breast cancer or pituitary tumor, a reproduction regulator, a contraceptive, an ovulation inducing agent or an agent for the prevention of post-operative recurrence of sex hormone-dependent cancers and the like.

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Claims (12)

  1. Dérivé hétérocyclique condensé représenté par la formule générale (I) :
    Figure imgb0071
    dans laquelle le cycle A représente un cycle thiophène ;
    RA représente un atome d'halogène, un groupe alkyle inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-1), -COOW1 ou -CONW2W3, où W1 à W3 représentent indépendamment un atome d'hydrogène ou un groupe alkyle inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-1), ou W2 et W3 se lient facultativement ensemble à l'atome d'azote voisin pour former un groupe amino cyclique qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (B-1) ;
    m représente un nombre entier égal à 0 ou 1 ;
    le cycle B représente un cycle benzène, un cycle thiophène ou un cycle pyridine ;
    RB représente un atome d'halogène, un groupe alkyle inférieur facultativement substitué par un atome d'halogène, ou -OW4 où W4 représente un atome d'hydrogène ou un groupe alkyle inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-2) ;
    n représente un nombre entier de 0 à 2 ;
    E1 représente un atome d'oxygène ;
    E2 représente un atome d'oxygène ;
    Q représente un atome d'hydrogène, un groupe alkyle inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-2), -COW7 ou -SO2W8;
    X représente un groupe représenté par -L-Z,
    où W7 représente un groupe alkyle inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-2), ou un groupe alcoxy inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-2) ;
    W8 représente un groupe alkyle inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-2) ;
    L représente un groupe alkylène inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-2) ;
    Z représente un groupe aryle facultativement condensé qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (C) ;
    et à condition que lorsque Z est un groupe aryle qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (C), le groupe aryle comprend au moins un substituant ;
    groupe substituant (A-1) : un atome d'halogène, un groupe cyano, un groupe hydroxy, un groupe alcoxy inférieur, un groupe (alkyle inférieur)thio, un groupe amino, un groupe (di)(alkyle inférieur)amino, un groupe carboxy, un groupe (alcoxy inférieur)carbonyle, un groupe carbamoyle et un groupe (di)(alkyle inférieur)carbamoyle ;
    groupe substituant (A-2) : un atome d'halogène, un groupe cyano, un groupe hydroxy, un groupe alcoxy inférieur, un groupe (alkyle inférieur)thio, un groupe amino, un groupe (di)(alkyle inférieur)amino, un groupe carboxy, un groupe (alcoxy inférieur)carbonyle, un groupe carbamoyle, un groupe (di)(alkyle inférieur)carbamoyle, un groupe aryle et un groupe hétéroaryle ;
    groupe substituant (B-1) : un groupe oxo, un atome d'halogène, un groupe cyano, un groupe hydroxy, un groupe alkyle inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-1), un groupe cycloalkyle, un groupe alcoxy inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-1), un groupe (alkyle inférieur)thio qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-1), un groupe carboxy, un groupe (alcoxy inférieur)carbonyle qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-1), un groupe carbamoyle, un groupe (di)(alkyle inférieur)carbamoyle et un groupe acylamino ;
    groupe substituant (C) : un atome d'halogène, un groupe nitro, un groupe cyano, un groupe hydroxy, un groupe alkyle inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-2), un groupe cycloalkyle, un groupe alcoxy inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-2), un groupe (alkyle inférieur)thio qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-2), un groupe carboxy, un groupe (alcoxy inférieur)carbonyle qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-2), un groupe carbamoyle, un groupe (di)(alkyle inférieur)carbamoyle, un groupe aryle, un groupe aryloxy, un groupe hétéroaryle, un groupe hétéroaryloxy et un groupe acylamino ;
    le terme alkyle inférieur signifie un groupe alkyle facultativement ramifié ayant de 1 à 6 atomes de carbone, le terme alkylène inférieur signifie un groupe alkylène facultativement ramifié ayant de 1 à 6 atomes de carbone et le terme alcoxy inférieur signifie un groupe alcoxy facultativement ramifié ayant de 1 à 6 atomes de carbone ;
    le terme aryle signifie un groupe phényle ;
    le terme hétéroaryle signifie un groupe hétéroaryle monocyclique ayant 1 ou plusieurs hétéroatomes choisis dans le groupe constitué par un atome d'azote, un atome d'oxygène et un atome de soufre ;
    le terme cycloalkyle signifie un groupe cycloalkyle monocyclique ayant de 3 à 8 atomes de carbone ;
    ou un sel pharmaceutiquement acceptable de celui-ci.
  2. Dérivé hétérocyclique condensé selon la revendication 1, dans lequel le cycle A est l'un quelconque des cycles thiophène représentés par les formules :
    Figure imgb0072
     ou un sel pharmaceutiquement acceptable de celui-ci.
  3. Dérivé hétérocyclique condensé selon la revendication 1 ou 2, dans lequel RA est un groupe alkyle inférieur substitué par un groupe choisi dans le groupe constitué par un groupe hydroxy, un groupe carboxy et un groupe carbamoyle ; un groupe carboxy ; ou un groupe carbamoyle, ou un sel pharmaceutiquement acceptable de celui-ci.
  4. Dérivé hétérocyclique condensé selon l'une quelconque des revendications 1 à 3, dans lequel m est 1 et le cycle A ayant RA sur le cycle est l'un quelconque des cycles thiophène représentés par les formules suivantes :
    Figure imgb0073
     ou un sel pharmaceutiquement acceptable de celui-ci.
  5. Dérivé hétérocyclique condensé selon l'une quelconque des revendications 1 à 4, dans lequel le cycle B est l'un quelconque des cycles représentés par les formules :
    Figure imgb0074
     ou un sel pharmaceutiquement acceptable de celui-ci.
  6. Dérivé hétérocyclique condensé selon la revendication 5, dans lequel n est 1 ou 2 et le cycle B ayant RB sur le cycle est l'un quelconque des cycles benzène, des cycles pyridine et des cycles thiophène représentés par les formules suivantes :
    Figure imgb0075
    Figure imgb0076
    Figure imgb0077
     dans les formules, RB a la même signification que définie dans la revendication 1, et lorsque deux RB sont présents, ces deux RB peuvent être identiques ou différents l'un de l'autre, ou un sel pharmaceutiquement acceptable de celui-ci.
  7. Dérivé hétérocyclique condensé selon la revendication 5 ou 6, dans lequel le cycle B est l'un quelconque des cycles représentés par les formules :
    Figure imgb0078
     ou un sel pharmaceutiquement acceptable de celui-ci.
  8. Dérivé hétérocyclique condensé selon l'une quelconque des revendications 1 à 7, dans lequel RB est un atome de fluor, un atome de chlore ou -OW4, où W4 est un groupe alkyle inférieur, ou un sel pharmaceutiquement acceptable de celui-ci.
  9. Dérivé hétérocyclique condensé selon l'une quelconque des revendications 1 à 8, dans lequel Q est un groupe alkyle inférieur qui peut comprendre n'importe quel substituant choisi dans le groupe substituant (A-2), ou un sel pharmaceutiquement acceptable de celui-ci.
  10. Dérivé hétérocyclique condensé selon l'une quelconque des revendications 1 à 9, dans lequel L est un groupe alkylène en C1 à C3, ou un sel pharmaceutiquement acceptable de celui-ci.
  11. Composition pharmaceutique comprenant en tant que principe actif un dérivé hétérocyclique condensé selon l'une quelconque des revendications 1 à 10, ou un sel pharmaceutiquement acceptable de celui-ci.
  12. Composition pharmaceutique selon la revendication 11, pour une utilisation dans la prévention ou le traitement d'une maladie dépendant des hormones sexuelles, en tant que régulateur de reproduction, contraception, agent induisant une ovulation ou agent de prévention d'une récurrence post-opératoire de cancers dépendant des hormones sexuelles.
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DE4131038A1 (de) 1991-09-20 1993-04-01 Basf Ag Substituierte 3-phenylurazile
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ATE280171T1 (de) 1998-12-23 2004-11-15 Bristol Myers Squibb Pharma Co Stickstoffhaltige heterobicyclen als faktor-xa- hemmer
EP1255738B1 (fr) * 2000-01-25 2012-03-07 Neurocrine Biosciences, Inc. Antagonistes du recepteur de la gonadoliberine et methodes associees
WO2005019188A1 (fr) 2003-08-22 2005-03-03 Takeda Pharmaceutical Company Limited Derive de pyrimidine fusionne et utilisation associee
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US20070010537A1 (en) * 2004-08-20 2007-01-11 Kazumasa Hamamura Fused pyramidine derivative and use thereof
WO2006083005A1 (fr) 2005-02-03 2006-08-10 Takeda Pharmaceutical Company Limited Dérivé de pyrimidine condensée et utilisation de celui-ci
EP1939204B3 (fr) 2005-10-19 2022-08-24 Kissei Pharmaceutical Co., Ltd. Dérivé hétérocyclique à cycles joints, préparation thérapeutique contenant ledit dérivé, et emploi thérapeutique dudit dérivé

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Title
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